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Naturally occurring SARS-CoV-2 gene deletions close to the spike S1/S2 cleavage site in the viral quasispecies of COVID19 patients

Cristina Andres, Damir Garcia-Cehic, Josep Gregori, Maria Piñana, Francisco Rodriguez-Frias, Mercedes Guerrero-Murillo, Juliana Esperalba, Ariadna Rando, Lidia Goterris, Maria Gema Codina, Susanna Quer, Maria Carmen Martín, Magda Campins, View ORCID ProfileRicard Ferrer, Benito Almirante, Juan Ignacio Esteban, Tomás Pumarola, Andrés Antón, Josep Quer
doi: https://doi.org/10.1101/2020.06.03.129585
Cristina Andres
1Respiratory Viruses Unit, Microbiology Department, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
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Damir Garcia-Cehic
2Liver Unit, Liver Diseases – Viral Hepatitis, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
3Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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Josep Gregori
3Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
4Roche Diagnostics SL, Sant Cugat del Valles, Barcelona, Spain
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Maria Piñana
1Respiratory Viruses Unit, Microbiology Department, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
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Francisco Rodriguez-Frias
3Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
5Biochemistry and Microbiology Departments, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
6Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
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Mercedes Guerrero-Murillo
2Liver Unit, Liver Diseases – Viral Hepatitis, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
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Juliana Esperalba
1Respiratory Viruses Unit, Microbiology Department, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
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Ariadna Rando
7Microbiology Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
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Lidia Goterris
7Microbiology Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
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Maria Gema Codina
7Microbiology Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
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Susanna Quer
2Liver Unit, Liver Diseases – Viral Hepatitis, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
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Maria Carmen Martín
1Respiratory Viruses Unit, Microbiology Department, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
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Magda Campins
8Preventive Medicine, Hospital Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
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Ricard Ferrer
9Intensive Care Department. Shock, Disfunció Orgànica i Ressuscitació (SODIR) Research Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
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  • ORCID record for Ricard Ferrer
Benito Almirante
10Infectious Diseases Department. Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
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Juan Ignacio Esteban
2Liver Unit, Liver Diseases – Viral Hepatitis, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
3Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
6Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
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Tomás Pumarola
6Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
7Microbiology Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
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Andrés Antón
1Respiratory Viruses Unit, Microbiology Department, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
6Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
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  • For correspondence: josep.quer@vhir.org josep.quer@ciberehd.org aanton@vhebron.net
Josep Quer
2Liver Unit, Liver Diseases – Viral Hepatitis, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain
3Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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  • For correspondence: josep.quer@vhir.org josep.quer@ciberehd.org aanton@vhebron.net
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ABSTRACT

The SARS-CoV-2 spike (S) protein, the viral mediator for binding and entry into the host cell, has sparked great interest as a target for vaccine development and treatments with neutralizing antibodies. Initial data suggest that the virus has low mutation rates, but its large genome could facilitate recombination, insertions, and deletions, as has been described in other coronaviruses. Here, we deep-sequenced the complete SARS-CoV-2 S gene from 18 patients (10 with mild and 8 with severe COVID-19), and found that the virus accumulates deletions upstream and very close to the S1/S2 cleavage site, generating a frameshift with appearance of a stop codon. These deletions were found in a small percentage of the viral quasispecies (2.2%) in samples from all the mild and only half the severe COVID-19 patients. Our results suggest that the virus may generate free S1 protein released to the circulation. We propose that natural selection has favored a “Don’t burn down the house” strategy, in which free S1 protein may compete with viral particles for the ACE2 receptor, thus reducing the severity of the infection and tissue damage without losing transmission capability.

Competing Interest Statement

The authors have declared no competing interest.

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Naturally occurring SARS-CoV-2 gene deletions close to the spike S1/S2 cleavage site in the viral quasispecies of COVID19 patients
Cristina Andres, Damir Garcia-Cehic, Josep Gregori, Maria Piñana, Francisco Rodriguez-Frias, Mercedes Guerrero-Murillo, Juliana Esperalba, Ariadna Rando, Lidia Goterris, Maria Gema Codina, Susanna Quer, Maria Carmen Martín, Magda Campins, Ricard Ferrer, Benito Almirante, Juan Ignacio Esteban, Tomás Pumarola, Andrés Antón, Josep Quer
bioRxiv 2020.06.03.129585; doi: https://doi.org/10.1101/2020.06.03.129585
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Naturally occurring SARS-CoV-2 gene deletions close to the spike S1/S2 cleavage site in the viral quasispecies of COVID19 patients
Cristina Andres, Damir Garcia-Cehic, Josep Gregori, Maria Piñana, Francisco Rodriguez-Frias, Mercedes Guerrero-Murillo, Juliana Esperalba, Ariadna Rando, Lidia Goterris, Maria Gema Codina, Susanna Quer, Maria Carmen Martín, Magda Campins, Ricard Ferrer, Benito Almirante, Juan Ignacio Esteban, Tomás Pumarola, Andrés Antón, Josep Quer
bioRxiv 2020.06.03.129585; doi: https://doi.org/10.1101/2020.06.03.129585

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